Chronic lung allograft dysfunction (CLAD) is the primary cause of mortality in lung transplant recipients beyond one year of transplant and includes bronchiolitis obliterans syndrome (BOS). Currently, there are no therapeutic agents available to prevent CLAD or BOS. Treatments are limited to supportive strategies with low and variable success rates once CLAD develops. ARINA-1, a patented formulation for a nebulized therapy of ascorbic acid (ASC), is designed to use when patients develop precursors to BOS, known as BOS-0p, rather than wait until it progresses to potentially unrecoverable pathology. As a patient develops BOS-0p, the physical and chemical barriers that typically maintain pulmonary health are compromised, making the lung more susceptible to irritants and bacteria in the environment. This initiates a cycle of inflammation and infection that leads to decreased pulmonary function and, ultimately, graft rejection and failure. ASC is critical to first-line airway defenses and is significantly depleted in the airway of patients who are post lung transplant. Thus, the mechanism of ARINA-1 therapy is simple: ARINA-1 delivers ASC directly to the lung, which restores the first lines of defense against inflammation and infection. In preclinical studies, we demonstrate that ARINA-1 both activates CFTR-mediated ion transport and mucus transport, decreases mucus viscosity and inflammation, and inhibits bacterial growth. Pilot studies in three patients with severe pulmonary disease demonstrate ARINA-1 safety and preliminary efficacy. A successful Phase 1 study in stable lung transplant patients confirmed ARINA-1 safety and prompted the FDA to permit an NDA-enabling Phase 2 clinical trial in patients with BOS-0p. The Aims of this proposal are designed to advance ARINA-1 to FDA approval for use in lung transplant patients with BOS-0p, for whom there are no current therapies. In this Direct-to-Phase II submission, we will conduct the NDA-enabling multi-center clinical trial to rigorously evaluate ARINA-1 efficacy in BOS-0p. The successful completion of these Aims will result in NDA filing for the first FDA-approved therapy for lung transplant patients with BOS-0p to prevent the progression to CLAD and graft failure. ARINA-1 approval will improve clinical practice for lung transplant care, by offering physicians a therapeutic option for treating BOS-0p before it progresses to CLAD, increasing not only survival, but also quality of life during the prolonged survival.